Prolonged Time to Surgery in Patients with Residual Disease After Neoadjuvant Chemoradiotherapy for Esophageal Cancer.

OBJECTIVE: To investigate whether prolonged time to surgery negatively affects survival, pathological outcome or postoperative complications in patients with histologically proven residual disease after neoadjuvant chemoradiotherapy for locally advanced esophageal cancer. SUMMARY BACKGROUND DATA: Historically, the standard time to surgery (TTS) has been six to eight weeks after completion of nCRT. The effect of prolonged TTS is gaining interest, with contradicting results on survival and surgical morbidity. It can be hypothesized that, in patients with residual disease six weeks after completion of nCRT, prolonged TTS might be associated with worse survival and higher morbidity. METHODS: Patients with locally advanced esophageal cancer who had biopsy-proven residual disease six weeks after nCRT and underwent surgery, were categorized according to interval to surgery (TTS>12w vs. TTS≤12w). Primary outcome of this study was overall survival. Secondary outcomes were disease-free survival, surgical outcomes, pathological outcomes, and postoperative complications. Multivariable Cox regression was used for comparing survival and logistic regression for other outcomes, adjusted for the confounders age, cT, cN, Charlson comorbidity index, weight loss during nCRT, and WHO performance score after completion of nCRT. RESULTS: Forty patients were included for TTS>12w and 127 for TTS≤12w. TTS>12w was associated with better overall survival (adjusted hazard ratio (aHR) 0.46, 95%CI 0.24-0.90), and disease-free survival (aHR 0.48, 95%CI 0.24-0.94), but also with more postoperative respiratory complications (aOR 3.66, 95%CI 1.52-9.59). Other outcomes were comparable between both groups. CONCLUSION: Prolonged TTS in patients with histologically proven residual disease after completion of nCRT for esophageal cancer did not have a negative effect on overall and disease-free survival, but patients did have a higher risk for postoperative respiratory complications.

Interval Metastases After Neoadjuvant Chemoradiotherapy for Patients with Locally Advanced Esophageal Cancer: A Multicenter Observational Cohort Study.

BACKGROUND: Despite trimodality treatment, 10% to 20% of patients with esophageal cancer experience interval metastases after surgery. Restaging may identify patients who should not proceed to surgery, as well as a subgroup with limited metastases for whom long-term disease-control can be obtained. This study aimed to determine the proportion of patients with interval metastases after neoadjuvant chemoradiotherapy (nCRT) and to evaluate treatment and survival. METHODS: Patients who had cT2-4aN0-3M0 esophageal cancer treated with nCRT were identified from a trial database. Metastases detected up to 14 weeks after nCRT on 18F-FDG-PET/CT or during surgery were categorized as oligometastases (≤3 lesions located in one single organ or one extra-regional lymph node station) or as non-oligometastases. The primary outcome was the proportion of patients with metastases after nCRT. The secondary outcomes were overall survival (OS) and the site and treatment of metastases. RESULTS: Between 2013 and 2021, 973 patients received nCRT, and 10.3% had interval metastases. Of 100 patients, 30 (30%) had oligometastases, located mostly in non-regional lymph nodes (33.3%) or bones (26.7%). The median OS of this group was 13.8 months (95% confidence interval [CI] 9.2-27.1 months). Of 30 patients, 12 (40%) with oligometastases underwent potentially curative treatment, with a median OS of 22.8 months (95% CI 10.4-NA). The patients with non-oligometastases underwent mostly systemic therapy or BSC and had a median OS of 9 months (95% CI 7.4-10.9 months). CONCLUSIONS: Interval metastases were detected in about 10% of patients after nCRT, underscoring the importance of re-staging with 18F-FDG-PET/CT for those who proceed to surgery. A favorable survival might be accomplished for a subgroup of patients with oligometastases.

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin: a systematic review and meta-analysis.

BACKGROUND: Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy. METHODS: Embase, MEDLINE, Web of Science and Cochrane were searched for articles studying the use of repeated administration of palliative intraperitoneal chemotherapy in patients with gastric cancer and peritoneal metastases, published up to January 2024. The primary outcome was overall survival. RESULTS: Twenty-three studies were included, representing a total of 999 patients. The pooled median overall survival was 14.5 months. The pooled hazard ratio of the two RCTs using intraperitoneal paclitaxel and docetaxel favoured the intraperitoneal chemotherapy arm. The median overall survival of intraperitoneal paclitaxel, intraperitoneal docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.4 months, 13.2 months and 9.0 months. All treatment methods had a relatively safe toxicity profile. Conversion surgery after completion of intraperitoneal therapy was performed in 16% of the patients. CONCLUSIONS: Repeated intraperitoneal chemotherapy, regardless of method of administration, is safe for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a subset of patients.

Pathological response to neoadjuvant chemoradiotherapy for oesophageal squamous cell carcinoma in Eastern versus Western countries: meta-analysis.

OBJECTIVE: Locally advanced oesophageal squamous cell carcinoma can be treated with neoadjuvant chemoradiotherapy or chemotherapy followed by oesophagectomy. Discrepancies in pathological response rates have been reported between studies from Eastern versus Western countries. The aim of this study was to compare the pathological response to neoadjuvant chemoradiotherapy in Eastern versus Western countries. METHODS: Databases were searched until November 2022 for studies reporting pCR rates after neoadjuvant chemoradiotherapy for oesophageal squamous cell carcinoma. Multi-level meta-analyses were performed to pool pCR rates separately for cohorts from studies performed in centres in the Sinosphere (East) or in Europe and the Anglosphere (West). RESULTS: For neoadjuvant chemoradiotherapy, 51 Eastern cohorts (5636 patients) and 20 Western cohorts (3039 patients) were included. Studies from Eastern countries included more men, younger patients, more proximal tumours, and more cT4 and cN+ disease. Patients in the West were more often treated with high-dose radiotherapy, whereas patients in the East were more often treated with a platinum + fluoropyrimidine regimen. The pooled pCR rate after neoadjuvant chemoradiotherapy was 31.7% (95% c.i. 29.5% to 34.1%) in Eastern cohorts versus 40.4% (95% c.i. 35.0% to 45.9%) in Western cohorts (fixed-effect P = 0.003). For cohorts with similar cTNM stages, pooled pCR rates for the East and the West were 32.5% and 41.9% respectively (fixed-effect P = 0.003). CONCLUSION: The pathological response to neoadjuvant chemoradiotherapy is less favourable in patients treated in Eastern countries compared with Western countries. Despite efforts to investigate accounting factors, the discrepancy in pCR rate cannot be entirely explained by differences in patient, tumour, or treatment characteristics.

Systemic Treatment Strategies and Outcomes of Patients With Synchronous Peritoneal Metastases of Gastric Origin: A Nationwide Population-Based Study.

BACKGROUND: Palliative systemic treatment is currently standard of care for metastatic gastric cancer. However, patients with peritoneal metastases of gastric origin are often underrepresented in clinical studies due to unmeasurable radiologic disease. This study describes the systemic treatment strategies and outcomes in patients with peritoneal metastases in a nationwide real-world setting. METHODS: Patients with gastric adenocarcinoma and synchronous peritoneal metastases (with or without other metastases) diagnosed in the Netherlands between 2015 and 2020 were identified from the nationwide Netherlands Cancer Registry. Median overall survival (OS) and time-to-treatment failure were determined and multivariable Cox regression analyses were used to compare treatment groups, corrected for relevant tumor and patient characteristics. RESULTS: In total, 1,972 patients were included, of whom 842 (43%) were treated with palliative systemic therapy. The majority received capecitabine + oxaliplatin (CAPOX; 44%), followed by fluorouracil/leucovorin/oxaliplatin (FOLFOX; 19%), and epirubicin + capecitabine + oxaliplatin (EOX; 8%). Of the 99 (45%) patients who received second-line systemic treatment, ramucirumab + paclitaxel were administered most frequently (63%). After adjustment for sex, age, comorbidities, performance status, tumor location, Lauren classification, and the presence of metastases outside of the peritoneum, patients treated with a triplet containing docetaxel and those treated with a regimen containing trastuzumab had a significantly longer OS compared with patients treated with a doublet containing a fluoropyrimidine derivate + oxaliplatin (hazard ratio [HR], 0.69; 95% CI, 0.52-0.91, and HR, 0.68; 95% CI, 0.51-0.91, respectively). Monotherapy was associated with a shorter OS (HR, 2.08, 95% CI, 1.53-2.83). CONCLUSIONS: There is substantial heterogeneity in systemic treatment choices in patients with gastric cancer and peritoneal metastases in the Netherlands. In this study, patients treated with triplets containing docetaxel and with trastuzumab-containing regimens survived longer than patients who received doublet therapy. Despite this, median OS for all treatment groups remained below one year.

N3 Disease in Esophageal Cancer: Results from a Nationwide Registry.

BACKGROUND: Patients with extensive lymph node metastases have a poor prognosis. Clinical staging of lymph node metastases poses significant challenges given the limited sensitivity and specificity of imaging techniques. The aim of this study was to investigate the overall survival (OS) of patients with N3 disease in a real-world Dutch population and the added value of surgery in these patients. METHODS: Patients with cN3M0 esophageal or gastroesophageal cancer were identified from the Netherlands Cancer Registry (2012-2019). Treatment consisted of neoadjuvant chemo(radio)therapy followed by resection or chemo(radio)therapy, radiotherapy, or esophagectomy alone. OS was calculated using the Kaplan-Meier method. RESULTS: Some 21,566 patients were diagnosed with esophageal cancer of whom 359 (1.7%) had cN3M0 disease. Median OS of these patients was 12.5 months (95% CI: 10.7-14.3). Median OS following chemoradiotherapy alone and neoadjuvant therapy plus surgery was 13.3 months (95% CI: 10.7-15.9) and 23.7 months (95% CI: 18.3-29.2), respectively. Of all patients who underwent esophagectomy, 391 (2.8%) had (y)pN3 disease, and median OS was 16.1 months (95% CI: 14.8-17.4). Twenty-one patients (5.4%) were correctly classified as cN3, and 3-year OS was 21%. CONCLUSION(S): Clinical staging appears to be difficult, apparently in patients with N3 esophageal cancer. Surgery seems to be of benefit to these patients. More research is required to address the ongoing challenges in clinical staging and the best neoadjuvant therapy.

Overall survival after definitive chemoradiotherapy for patients with esophageal cancer: a retrospective cohort study.

Definitive chemoradiotherapy (dCRT) is a potentially curative therapy for esophageal cancer. As indications for dCRT differ widely, it is challenging to draw conclusions on outcomes and survival. The aim of this study was to evaluate overall survival (OS) and recurrence patterns according to indications for treatment. Patients who underwent dCRT (50.4 Gy concomitant with carboplatin/paclitaxel) for esophageal cancer between 2012 and 2022 were identified. Indications for dCRT were: cervical tumor, irresectable disease, unfit for surgery, and patient and/or physician preference. The primary endpoint was OS calculated with the Kaplan-Meier method. Secondary endpoints included the proportion of patients that completed the dCRT regimen, 30- and 90-day mortality, and disease recurrence. One hundred and fifty-seven patients were included (72.6% esophageal squamous cell carcinoma) with a median follow-up of 20 months (IQR 10.0-43.9). The full dCRT regimen was completed by 116 patients (73.9%). Thirty- and 90-day mortality were 2.5% and 8.3%, respectively. Median and 5-year OS for all patients were 22.9 months (95% CI 18.0-27.9) and 31.4%, respectively. The median OS per indication was 23.7 months (95% CI 6.5-40.8) for patients with cervical tumors, 10.9 months (95% 0.0-23.2) for irresectable disease, 28.2 months (95% CI 12.3-44.0) for unfit patients, and 22.9 months (95% CI 15.4-30.5) for patients' preference for dCRT (P = 0.11). Disease recurrence was observed in 74 patients (46%), located locoregionally (46%), distant (19%), or combined (35%). Patients who underwent dCRT had a 5-year OS of 31.4%, but OS differed according to indications for treatment with patients who had irresectable disease having the worst prognosis.

Active surveillance of oesophageal cancer after response to neoadjuvant chemoradiotherapy: dysphagia is uncommon.

BACKGROUND: Active surveillance is being investigated as an alternative to standard surgery after neoadjuvant chemoradiotherapy for oesophageal cancer. It is unknown whether dysphagia persists or develops when the oesophagus is preserved after neoadjuvant chemoradiotherapy. The aim of this study was to assess the prevalence and severity of dysphagia during active surveillance in patients with an ongoing response. METHODS: Patients who underwent active surveillance were identified from the Surgery As Needed for Oesophageal cancer ('SANO') trial. Patients without evidence of residual oesophageal cancer until at least 6 months after neoadjuvant chemoradiotherapy were included. Study endpoints were assessed at time points that patients were cancer-free and remained cancer-free for the next 4 months. Dysphagia scores were evaluated at 6, 9, 12, and 16 months after neoadjuvant chemoradiotherapy. Scores were based on the European Organisation for Research and Treatment of Cancer oesophago-gastric quality-of-life questionnaire 25 (EORTC QLQ-OG25) (range 0-100; no to severe dysphagia). The rate of patients with a (non-)traversable stenosis was determined based on all available endoscopy reports. RESULTS: In total, 131 patients were included, of whom 93 (71.0 per cent) had adenocarcinoma, 93 (71.0 per cent) had a cT3-4a tumour, and 33 (25.2 per cent) had a tumour circumference of greater than 75 per cent at endoscopy; 60.8 to 71.0 per cent of patients completed questionnaires per time point after neoadjuvant chemoradiotherapy. At all time points after neoadjuvant chemoradiotherapy, median dysphagia scores were 0 (interquartile range 0-0). Two patients (1.5 per cent) underwent an intervention for a stenosis: one underwent successful endoscopic dilatation; and the other patient required temporary tube feeding. Notably, these patients did not participate in questionnaires. CONCLUSION: Dysphagia and clinically relevant stenosis are uncommon during active surveillance.

A prospective cohort study on active surveillance after neoadjuvant chemoradiotherapy for esophageal cancer: protocol of Surgery As Needed for Oesophageal cancer-2.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is a standard treatment for potentially curable esophageal cancer. Active surveillance in patients with a clinically complete response (cCR) 12 weeks after nCRT is regarded as possible alternative to standard surgery. The aim of this study is to monitor the safety, adherence and effectiveness of active surveillance in patients outside a randomized trial. METHODS: This nationwide prospective cohort study aims to accrue operable patients with non-metastatic histologically proven adenocarcinoma or squamous cell carcinoma of the esophagus or esophagogastric junction. Patients receive nCRT and response evaluation consists of upper endoscopy with bite-on-bite biopsies, endoscopic ultrasonography plus fine-needle aspiration of suspicious lymph nodes and 18F-fluorodeoxyglucose positron emission tomography/computed tomography scan. When residue or regrowth of tumor in the absence of distant metastases is detected, surgical resection is advised. Patients with cCR after nCRT are suitable to undergo active surveillance. Patients can consult an independent physician or psychologist to support decision-making. Primary endpoint is the number and severity of adverse events in patients with cCR undergoing active surveillance, defined as complications from response evaluations, delayed surgery and the development of distant metastases. Secondary endpoints include timing and quality of diagnostic modalities, overall survival, progression-free survival, fear of cancer recurrence and decisional regret. DISCUSSION: Active surveillance after nCRT may be an alternative to standard surgery in patients with esophageal cancer. Similar to organ-sparing approaches applied in other cancer types, the safety and efficacy of active surveillance needs monitoring before data from randomized trials are available. TRIAL REGISTRATION: The SANO-2 study has been registered at ClinicalTrials.gov as NCT04886635 (May 14, 2021) - Retrospectively registered.

Worldwide Techniques and Outcomes in Robot-assisted Minimally Invasive Esophagectomy (RAMIE): Results From the Multicenter International Registry.

OBJECTIVE: This international multicenter study by the Upper GI International Robotic Association aimed to gain insight in current techniques and outcomes of RAMIE worldwide. BACKGROUND: Current evidence for RAMIE originates from single-center studies, which may not be generalizable to the international multicenter experience. METHODS: Twenty centers from Europe, Asia, North-America, and South-America participated from 2016 to 2019. Main endpoints included the surgical techniques, clinical outcomes, and early oncological results of ramie. RESULTS: A total of 856 patients undergoing transthoracic RAMIE were included. Robotic surgery was applied for both the thoracic and abdominal phase (45%), only the thoracic phase (49%), or only the abdominal phase (6%). In most cases, the mediastinal lymphadenectomy included the low paraesophageal nodes (n=815, 95%), subcarinal nodes (n = 774, 90%), and paratracheal nodes (n = 537, 63%). When paratracheal lymphadenectomy was performed during an Ivor Lewis or a McKeown RAMIE procedure, recurrent laryngeal nerve injury occurred in 3% and 11% of patients, respectively. Circular stapled (52%), hand-sewn (30%), and linear stapled (18%) anastomotic techniques were used. In Ivor Lewis RAMIE, robot-assisted hand-sewing showed the highest anastomotic leakage rate (33%), while lower rates were observed with circular stapling (17%) and linear stapling (15%). In McKeown RAMIE, a hand-sewn anastomotic technique showed the highest leakage rate (27%), followed by linear stapling (18%) and circular stapling (6%). CONCLUSION: This study is the first to provide an overview of the current techniques and outcomes of transthoracic RAMIE worldwide. Although these results indicate high quality of the procedure, the optimal approach should be further defined.

Transthoracic esophagectomy compared to transhiatal extended gastrectomy for adenocarcinoma of the esophagogastric junction: a multicenter retrospective cohort study.

Optimal surgical treatment for Siewert type II esophagogastric junction adenocarcinoma is debated. The aim of this study was to compare transhiatal extended gastrectomy (TEG) and transthoracic esophagectomy (TTE). Patients with Siewert type II tumors who underwent a resection by TEG or TTE in two centers (Erasmus University Medical Center, Rotterdam, and University of Verona) between 2014 and 2019 were identified. To limit selection bias, patients were matched for baseline characteristics and compared with a multivariable logistic regression model. Some 159 patients treated by TEG (60 patients, 37.7%) or TTE (99 patients, 62.3%) were included. Patients in the TEG group were older, had less tumor invasion of the esophagus, and were more often excluded from neoadjuvant therapy. Post-operative morbidity was comparable (P = 0.88), while 90-day mortality was higher after TEG (90-day mortality 10.0% in TEG group vs. 2.0% in TTE group P = 0.01). R0 resection was achieved in 83.3% of patients after TEG and in 97.9% after TTE (P < 0.01), with the proximal resection margin involved in 16.6% of patients after TEG versus 0 in TTE group (P < 0.01). The 3-year overall survival was comparable (TEG: 36.5%, TTE: 48.4%, P = 0.12). At multivariable analysis, (y)pT category was an independent risk factor for 3-year recurrence. After matching, TEG was still associated with an increased risk of incomplete tumor resection (P = 0.03) and proximal margin involvement (P < 0.01), while there were no differences in post-operative morbidity (P = 0.56) and mortality (P = 0.31). Our data suggest that patients with Siewert type II tumors treated by TEG are exposed to a higher risk of positive proximal resection margin compared to TTE.

The Effect of Postoperative Complications After Minimally Invasive Esophagectomy on Long-term Survival: An International Multicenter Cohort Study.

BACKGROUND: Esophagectomy is a technically challenging procedure, associated with significant morbidity. The introduction of minimally invasive esophagectomy (MIE) has reduced postoperative morbidity. OBJECTIVE: Although the short-term effect on complications is increasingly being recognized, the impact on long-term survival remains unclear. This study aims to investigate the association between postoperative complications following MIE and long-term survival. METHODS: Data were collected from the EsoBenchmark Collaborative composed by 13 high-volume, expert centers routinely performing MIE. Patients operated between June 1, 2011 and May 31, 2016 were included. Complications were graded using the Clavien-Dindo (CD) classification. To correct for short-term effects of postoperative complications on mortality, patients who died within 90 days postoperative were excluded. Primary endpoint was 5-year overall survival. RESULTS: A total of 915 patients were included with a mean follow-up time of 30.8 months (standard deviation 17.9). Complications occurred in 542 patients (59.2%) of which 50.2% had a CD grade ≥III complication [ie, (re)intervention, organ dysfunction, or death]. The incidence of anastomotic leakage (AL) was 135 of 915 patients (14.8%) of which 84 patients were classified as a CD grade ≥III. Multivariable analysis showed a significantly deteriorated long-term survival in all patients with AL [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.25-2.24]. This inverse relation was most distinct when AL was scored as a CD grade ≥III (HR 1.83, 95% CI 1.30-2.58). For all other complications, no significant association with long-term survival was found. CONCLUSION: The occurrence and severity of AL, but not overall complications, after MIE negatively affect long-term survival of esophageal cancer patients.

A structured training pathway to implement robot-assisted minimally invasive esophagectomy: the learning curve results from a high-volume center.

To ensure safe implementation of robot-assisted minimally invasive esophagectomy (RAMIE), the learning process should be optimized. This study aimed to report the results of a surgeon who implemented RAMIE in a German high-volume center by following a tailored and structured training pathway that involved proctoring. Consecutive patients who underwent RAMIE during the course of the program were included from a prospective database. A single surgeon, who had prior experience in conventional MIE, performed all RAMIE procedures. Cumulative sum (CUSUM) learning curves were plotted for the thoracic operating time and intraoperative blood loss. Perioperative outcomes were compared between patients who underwent surgery before and after a learning curve plateau occurred. Between 2017 and 2018, the adopting center adhered to the structured training pathway, and a total of 70 patients were included in the analysis. The CUSUM learning curves showed plateaus after 22 cases. In consecutive cases 23 to 70, the operating time was shorter for both the thoracic phase (median 215 vs. 249 minutes, P = 0.001) and overall procedure (median 394 vs. 440 minutes, P = 0.005), intraoperative blood loss was less (median 210 vs. 400 milliliters, P = 0.029), and lymph node yield was higher (median 32 vs. 23 nodes, P = 0.001) when compared to cases 1 to 22. No significant differences were found in terms of conversion rates, postoperative complications, length of stay, completeness of resection, or mortality. In conclusion, the structured training pathway resulted in a short and safe learning curve for RAMIE in this single center's experience. As the pathway seems effective in implementing RAMIE without compromising the early oncological outcomes and complication rates, it is advised for surgeons who are wanting to adopt this technique.

Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open esophagectomy: long-term follow-up of a randomized clinical trial.

Initial results of the ROBOT, which randomized between robot-assisted minimally invasive esophagectomy (RAMIE) and open transthoracic esophagectomy (OTE), showed significantly better short-term postoperative outcomes in favor of RAMIE. However, it is not yet clarified if RAMIE is equivalent to OTE regarding long-term outcomes. The aim of this study was to report the long-term oncological results of the ROBOT trial in terms of survival and disease-free survival. This study is a follow-up study of the ROBOT trial, which was a randomized controlled trial comparing RAMIE to OTE in 112 patients with intrathoracic esophageal cancer. Both the trial protocol and short-term results were previously published. The primary outcome of the current study was 5-year overall survival. Secondary outcomes were disease-free survival and recurrence patterns. Analysis was by intention to treat. During the recruitment period, 109 patients were included in the survival analysis (RAMIE n = 54, OTE n = 55). Majority of patients had clinical stage III or IV (RAMIE 63%, OTE 55%) and received neoadjuvant chemoradiotherapy (80%). Median follow-up was 60 months (range 31-60). The combined 5-year overall survival rates for RAMIE and OTE were 41% (95% CI 27-55) and 40% (95% CI 26-53), respectively (log rank test P = 0.827). The 5-year disease-free survival rate was 42% (95% CI 28-55) in the RAMIE group and 43% (95% CI 29-57) in the OTE group (log rank test P = 0.749). Out of 104 patients, 57 (55%) developed recurrent disease detected at a median of 10 months (range 0-56) after surgery. No statistically difference in recurrence rate nor recurrence pattern was observed between both groups. Overall survival and disease-free survival of RAMIE are comparable to OTE. These results continue to support the use of robotic surgery for esophageal cancer.

Robot-assisted Minimally Invasive Thoracolaparoscopic Esophagectomy Versus Open Transthoracic Esophagectomy for Resectable Esophageal Cancer: A Randomized Controlled Trial.

BACKGROUND: The standard curative treatment for patients with esophageal cancer is perioperative chemotherapy or preoperative chemoradiotherapy followed by open transthoracic esophagectomy (OTE). Robot-assisted minimally invasive thoracolaparoscopic esophagectomy (RAMIE) may reduce complications. METHODS: A single-center randomized controlled trial was conducted, assigning 112 patients with resectable intrathoracic esophageal cancer to either RAMIE or OTE. The primary endpoint was the occurrence of overall surgery-related postoperative complications (modified Clavien-Dindo classification grade 2-5). RESULTS: Overall surgery-related postoperative complications occurred less frequently after RAMIE (59%) compared to OTE (80%) [risk ratio with RAMIE (RR) 0.74; 95% confidence interval (CI), 0.57-0.96; P = 0.02]. RAMIE resulted in less median blood loss (400 vs 568 mL, P <0.001), a lower percentage of pulmonary complications (RR 0.54; 95% CI, 0.34-0.85; P = 0.005) and cardiac complications (RR 0.47; 95% CI, 0.27-0.83; P = 0.006) and lower mean postoperative pain (visual analog scale, 1.86 vs 2.62; P < 0.001) compared to OTE. Functional recovery at postoperative day 14 was better in the RAMIE group [RR 1.48 (95% CI, 1.03-2.13; P = 0.038)] with better quality of life score at discharge [mean difference quality of life score 13.4 (2.0-24.7, p = 0.02)] and 6 weeks postdischarge [mean difference 11.1 quality of life score (1.0-21.1; P = 0.03)]. Short- and long-term oncological outcomes were comparable at a medium follow-up of 40 months. CONCLUSIONS: RAMIE resulted in a lower percentage of overall surgery-related and cardiopulmonary complications with lower postoperative pain, better short-term quality of life, and a better short-term postoperative functional recovery compared to OTE. Oncological outcomes were comparable and in concordance with the highest standards nowadays.

Sample size of surgical randomized controlled trials: a lack of improvement over time.

BACKGROUND: Interpretation of randomized controlled trials (RCTs) without a significant difference regarding the primary outcome (negative RCTs) is frequently challenging, due to concerns about sample size and thus sufficient statistical power. We aimed to assess the adequacy of sample size and corresponding power of surgical RCTs. METHODS: We previously identified all surgical RCTs available in PubMed in two distinct years a decade apart (1999 and 2009). For all "negative" trials, we estimated whether the sample size of the trial was appropriate to detect a difference in the primary outcome measure. The main outcome measure was a sufficient sample size to detect large, medium, and small treatment effects. We also performed a post hoc power analysis based on the actual observed effect difference. RESULTS: A total of 228 negative RCTs (74 in 1999 and 121 in 2009) were included. The median sample size was 76 (± 222) and 80 (± 163) in 1999 and 2009, respectively. Sample size calculation was increasingly reported from 40% in 1999 to 54% in 2009 (P = 0.02). The proportion of studies adequately powered to detect large (57% versus 68%), medium (26% versus 25%), or small (8% versus 7%) differences did not differ significantly between 1999 and 2009, respectively. To reach sufficient power, the required increases in sample size were 130%, 240%, and 1032% for large, medium, and small differences, respectively. Reporting a sample size calculation was the only independent predictor for adequate power. CONCLUSIONS: Despite slight improvement in the reporting of a sample size calculation, about a third of surgical trials remains underpowered to demonstrate differences that are likely to be clinically significant. Increased attention of researchers, medical ethical boards, and journal editors is required to reduce potentially wasted resources on underpowered trials.

Perioperative chemotherapy versus neoadjuvant chemoradiotherapy for esophageal or GEJ adenocarcinoma: A propensity score-matched analysis comparing toxicity, pathologic outcome, and survival.

OBJECTIVES: To evaluate toxicity, pathologic outcome, and survival after perioperative chemotherapy (pCT) compared to neoadjuvant chemoradiotherapy (nCRT) followed by surgery for patients with resectable esophageal or gastroesophageal junction (GEJ) adenocarcinoma. METHODS: Consecutive patients with resectable esophageal or GEJ adenocarcinoma who underwent pCT (epirubicin, cisplatin, and capecitabine) or nCRT (paclitaxel, carboplatin, and 41.4 Gy) followed by surgery in a tertiary referral center in the Netherlands were compared. Propensity score matching was applied to create comparable groups. RESULTS: Of 193 eligible patients, 21 were discarded after propensity score matching; 86 and 86 patients who underwent pCT and nCRT, respectively, remained. Grade ≥3 thromboembolic events occurred only in the pCT group (19% vs. 0%, P < 0.001), whereas grade ≥3 leukopenia occurred more frequently in the nCRT group (14% vs. 4%, P = 0.015). No significant differences regarding postoperative morbidity and mortality were found. Pathologic complete response was more frequently observed with nCRT (18% vs. 11%, P < 0.001), without significantly improving radicality rates (95% vs. 89%, P = 0.149). Both strategies resulted in comparable 3-year progression-free survival (pCT vs. nCRT: 46% vs. 55%, P = 0.344) and overall survival rates (49% vs. 50%, P = 0.934). At 3-year follow-up, fewer locoregional disease progression occurred in the nCRT group (19% vs. 37%, P = 0.024). CONCLUSIONS: Compared to perioperative chemotherapy, neoadjuvant chemoradiotherapy achieves higher pathologic response rates and a lower risk of locoregional disease progression, without improving survival.

Journal impact factor and methodological quality of surgical randomized controlled trials: an empirical study.

PURPOSE: The journal impact factor (IF) is often used as a surrogate marker for methodological quality. The objective of this study is to evaluate the relation between the journal IF and methodological quality of surgical randomized controlled trials (RCTs). METHODS: Surgical RCTs published in PubMed in 1999 and 2009 were identified. According to IF, RCTs were divided into groups of low (<2), median (2-3) and high IF (>3), as well as into top-10 vs all other journals. Methodological quality characteristics and factors concerning funding, ethical approval and statistical significance of outcomes were extracted and compared between the IF groups. Additionally, a multivariate regression was performed. RESULTS: The median IF was 2.2 (IQR 2.37). The percentage of 'low-risk of bias' RCTs was 13% for top-10 journals vs 4% for other journals in 1999 (P < 0.02), and 30 vs 12% in 2009 (P < 0.02). Similar results were observed for high vs low IF groups. The presence of sample-size calculation, adequate generation of allocation and intention-to-treat analysis were independently associated with publication in higher IF journals; as were multicentre trials and multiple authors. CONCLUSION: Publication of RCTs in high IF journals is associated with moderate improvement in methodological quality compared to RCTs published in lower IF journals. RCTs with adequate sample-size calculation, generation of allocation or intention-to-treat analysis were associated with publication in a high IF journal. On the other hand, reporting a statistically significant outcome and being industry funded were not independently associated with publication in a higher IF journal.

A new clinical scoring system to define pneumonia following esophagectomy for cancer.

BACKGROUND: Pneumonia is a frequently observed complication following esophagectomy. The lack of a uniform definition of pneumonia leads to large variations of pneumonia rates in literature. This study was designed to develop a scoring system for diagnosing pneumonia following esophagectomy at the hospital ward. METHODS: In a prospective cohort study of esophagectomy patients, known risk factors for pneumonia, temperature, leukocyte count, pulmonary radiography and sputum culture added were evaluated. Primary outcome was defined as the decision to treat suspected pneumonia. Multivariate Cox regression analysis with backward selection was used to identify predictors of pneumonia treatment. RESULTS: The majority of postoperative pneumonia treatments (88.2%) occurred at the hospital ward, where treatment was observed in 67 (36.2%) of 185 patients. Independent diagnostic determinants for pneumonia treatment were temperature (hazard ratio (HR) = 1.283, p = 0.073), leukocyte count (HR = 1.040, p = 0.078) and pulmonary radiography (HR >11.0, p = 0.000). Sputum culture did not influence the decision to treat pneumonia. These findings were used to develop a scoring system which includes temperature, leukocyte count and pulmonary radiography. CONCLUSION: The decision to treat pneumonia is based on temperature, leukocyte count and pulmonary radiography findings. The proposed clinical scoring system for pneumonia following esophagectomy at the hospital ward has the potential to aid clinical practice and improve comparability of future research in esophageal cancer surgery.

Decision-making experiences of patients and partners opting for active surveillance in esophageal cancer treatment.

OBJECTIVES: This study explored the decision-making experiences of patients and their partners or primary caregiver who opted for experimental active surveillance (instead of standard surgery) for the treatment of esophageal cancer. METHODS: Seventeen couples participated. Semi-structured interviews were conducted on couples' joint experiences as well as their individual experiences. Preferred and perceived role in the treatment decision-making process was assessed using the adjusted version of the Control Preferences Scale, and perceived influence on the treatment decision was measured using a visual analog scale. RESULTS: Couples reflected on the decision-making process as a positive collaboration, where patients retain their autonomy by making the final decision, and partners offer emotional support. Couples reported about an overwhelming amount and sometimes conflicting information about treatments among different hospitals and healthcare providers. CONCLUSIONS: Patients often involve their partner in decision-making, which they report to have enhanced their ability to cope with the disease. The amount and sometimes conflicting information during the decision-making process provide opportunities for improvement. PRACTICE IMPLICATIONS: Couples can benefit from an overview of what they can expect during treatment course. If active surveillance becomes an established treatment option in the future, provision of such overviews and consistent information should become more streamlined.